The present invention relates to the synthesis of highly cross-linked polymers in scCO2, i.e. supercritical carbon dioxide.
Macroporous cross-linked polymer resins are usefull in a wide range of applications, including solid-phase synthesis, combinatorial chemistry, polymer-supported reagents, molecular imprinting, and size-exclusion chromatography. In the past, it has been common to produce these cross-linked polymer resins either as irregular particles or microspherical beads by heterogeneous polymerisation techniques such as suspension, emulsion, precipitation, and dispersion polymerisation; see Arshady, Colloid Polym. Sci. (1992) 270:717. More recently, it has become clear that, for certain applications, there are distinct advantages in producing cross4inked polymer resins in the form of highly porous continuous blocks, or xe2x80x98monolithsxe2x80x99; see Svec et al., Science (1996) 273:205; Peters et al., Anal. Chem. (1997) 69:3646; and also the review by Peters et al, Adv. Materials (1999) 11(14):1169.
Supercritical carbon dioxide (scCO2) is an attractive solvent for polymer chemistry because it is inexpensive, non-toxic, and non-flammable. Unlike conventional liquid solvents, scCO2 is highly compressible and the density (and therefore solvent properties) can be tuned over a wide range by varying pressure. Moreover, scCO2 reverts to the gaseous state upon depressurisation, greatly simplifying the separation of solvent from solute(s). scCO2 has been used as a solvent medium for homogeneous polymerisations [DeSimone et al., Science (1992) 257:945; and PCT/US93/01626] and heterogeneous precipitation polymerisations [Romack et al., Macromolecules (1995) 28:912]. Polymeric surfactants or stabilisers have been developed, which allow the synthesis of CO2-insoluble polymers in scCO2 in high yields by dispersion polymerisation; see DeSimone et al., Science (1994) 265:356; Canelas et al., Macromolecules (1997) 30:5673; and U.S. Pat. No. 5,679,737. All of these examples relate to the polymerisation in scCO2 of monomers containing a single polymerisable functional group (e.g., styrene, methyl methacrylate, acrylic acid).
DE-A-3609829 and U.S. Pat. No. 4,748,220 disclose forming cross-linked polymer particles in liquid or supercritical CO2. The polymers were formed as non-porous pulverent powders with primary particles in the size range 0.5-3 xcexcm.
U.S. Pat. No. 5,629,353 describes the use of a range of supercritical fluid solvents in various stages of the processing and/or formation of cross-linked nanoporous polymers. Their use in preparing microcellular cross-linked foams is described in U.S. Pat. Nos. 5,128,382, 5,252,620, and 5,066,684.
Cooper et al., Macromol. Rapid Commun. (1998) 19:353, describes the formation of regular non-porous cross-linked poly(divinyl benzene) microspheres in supercritical CO2 by heterogeneous polymerisation, both with and without the use of polymeric surfactants. This work is also disclosed in WO-A-99/38820 (published after the priority date claimed herein), where it is suggested that the polymerisation of divinylbenzene, trimethylolpropanetrimethacrylate or ethylene glycol dimethacrylate may be conducted, optionally with a copolymerisable monomer and optionally in the presence of a surfactant, at a monomer concentration of 15-40% vol % in CO2. In the Examples, the monomer concentration is 20 vol %.
The present invention is based on the discovery that a range of cross-linked polymers can be formed using scCO2 as the polymerisation medium, using multi-functional monomers containing two or more polymerisable functional groups, and that the polymers can be isolated in high yields directly from the reaction vessel as dry materials, surprisingly in the form of macroporous/mesoporous polymer monoliths with variable, well-controlled pore size distributions. The concentration of the monomer in CO2 should be above 40 vol %.
The pore size of the polymer monolith can be tuned, by varying the monomer concentration and/or by varying the CO2 density. It may also be tuned by conducting the polymerisation in the presence of a water-in-CO2 emulsion.
The cross-linked polymers are useful in a variety of potential applications, including molecular imprinting, solid phase synthesis, combinatorial chemistry, polymer-supported reagents, size exclusion chromatography, and supercritical fluid chromatography.
The process of the invention provides porous cross-linked polymer monoliths, preferably using volume percentages of monomer-in-CO2 in the range 40-60%, most preferably in the range 50-60%. The cross-linked polymers can be isolated as dry, macroporous/mesoporous monoliths, directly from the reactor. Since the solvent, CO2, reverts to a gas upon depressurisation, no solvent residues are left in the resulting cross-linked polymers and the use of VOC solvents is avoided.
The most preferred monomers are trimethylol propane trimethacrylate and ethylene glycol dimethacrylate. Another suitable monomer is divinylbenzene. Other suitable cross-linking agents are CO2-soluble bi-/multi-functional methacrylate monomers, bi-/multi-functional acrylate monomers, bi-/multi-functional allyl ether monomers, bi-/multi-functional epoxide monomers, bi-/multi-functional oxetane monomers, and bi-/multi-functional isocyanate monomers.
Highly cross-linked copolymers may be obtained by copolymerisation using the cross-linker with comonomers that contain reactive functional groups. Suitable comonomers include methacrylate and acrylate-based comonomers containing alkyl fluoroalkyl, poly(dimethyl siloxane) chains, low molecular weight poly(ethylene glycol) chains, perfluoropolyetherchains, alkyl halides, acid halides (e.g., methacryloyl chloride), alcohols (alkyl and aryl), protected alcohols (alkyl and aryl), esters (alkyl and aryl), aldehydes (alkyl and aryl), amines (alkyl and aryl), amides (alkyl and aryl), crown ethers, porphyrins, template groups for molecular imprinting, hygroscopic groups for the formation of superabsorbent polymers, functional groups for affinity chromatography, derivatisable functional groups for parallel synthesis, organic dyes, inorganic/organic reagents for organic synthesis, and transition metal/main group metal catalysts. Preferably, the comonomer includes a carboxylic acid group, e.g. methacrylic acid. The proportion of any such comonomer will typically be from 10 to 80%, preferably up to 50%, and more preferably 20%, w/w of the total monomers.
The polymerisation procedure works efficiently in scCO2 when thermal free radical initiation is used, employing 2,2xe2x80x2-azobisisobutyronitrile (AIBN) as the preferred initiator, e.g. at 50xc2x0 C. Other initiators that may be used are other free radical initiators (either thermally or photochemically decomposed), and cationic initiators in the case of ring-opening polymerisations of oxirane/oxetane based cross-linking monomers.
The cross-linked polymer monoliths are formed as continuous porous rods which conform to the cylindrical shape of the internal reactor volume. Continuous macroporous monoliths may also be formed (or xe2x80x98mouldedxe2x80x99) in other high-pressure vessels, such as wide-bore chromatography columns and narrow-bore silica/PEEK capillaries, in order to form novel continuous chromatography packings.
Carbon dioxide acts as an efficient, non-solvating porogenic solvent for the introduction of porosity in the polymer monoliths. The average pore diameter and pore size distribution can be varied over a wide range by changing the volume ratio of monomer to carbon dioxide; see in particular Table 2. The Examples show that an increase in the CO2-to-monomer ratio leads to larger pore sizes for the resultant polymers. Furthermore, the polymers can have relatively narrow and unimodal pore size distributions.
The monolithic polymers may subsequently be derivatised by covalent reactions such as nucleophilic, electrophilic, radical substitution or addition)or grafting reaction), or non-covalent bonding (electrostatic interactions, H-bonding, pi-pi stacking) with additional chemical functionality by passing chemical reagents through the porous channels, either as solutions in organic solvents or as solutions in supercritical CO2. This is advantageous, particularly in cases where conventional derivatisation techniques employing reactive hydrophilic or aqueous solvents are incompatible with the desired chemical functionality or polymer matrix.
In one embodiment of the invention, the polymerisation is carried out directly within a chromatography column in order to form a chromatographic packing material in situ. This may be for separations where the solvent is compressed CO2 or a conventional aqueous or non-aqueous solvent.
In another embodiment, the monolith is chemically derivatised by flowing a solution of a chemical reagent in a solvent through the porous material. This solvent may be scCO2 or a conventional aqueous or non-aqueous solvent.
Monoliths produced according to the invention have a variety of uses. For example, such a monolith may be used as a support for solid phase synthesis, as a support for polymeric reagents and scavengers, for solid phase extraction, for solid phase detection, for high-throughput screening, for on-chip separations, for molecular imprinting, for molecular recognition, as a high throughput bioreactor, or as a stationary phase for high performance liquid chromatography, supercritical fluid chromatography, high performance membrane chromatography or capillary electrochromatography.